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Class II histone deacetylases (HDAC4, HDAC5, HDAC7 and HDAC9) have been shown to interact with myocyte enhancer factors 2 (MEF2s) and play an important role in the repression of cardiac hypertrophy. We examined the role of HDACs during the differentiation of P19 embryonic carcinoma stem cells into cardiomyoctyes. Treatment of aggregated P19 cells with the HDAC inhibitor trichostatin A induced the entry of mesodermal cells into the cardiac muscle lineage, shown by the upregulation of transcripts Nkx2-5, MEF2C, GATA4 and cardiac α-actin. Furthermore, the overexpression of HDAC4 inhibited cardiomyogenesis, shown by the downregulation of cardiac muscle gene expression. Class II HDAC activity is inhibited through phosphorylation by Ca²⁺/calmodulin-dependent kinase (CaMK). Expression of an activated CaMKIV in P19 cells upregulated the expression of Nkx2-5, GATA4 and MEF2C, enhanced …